Cyclic imides of 3-substituted 2,4,6-triiodoanilines

ABSTRACT

Cyclic imides and anilic acids of 2,4,6-triiodoanilines bearing a substituted amino group in the 3-position are prepared by decarboxylation of the corresponding compounds bearing a carboxyl group in the 5-position. The products are useful as intermediates and as cholecystographic agents.

Unlted States Patent (1 1 m1 3,926,975

Ackerman Dec. 16, 1975 CYCLIC IMIDES OF 3-SUBSTITUTED {5 l] Int. Cl. C07d 87/34; C07d 93/ I0 2,4,6-TR1IODOANILINES l58] Field of Search 260/244, 243; 424/5 [75] Inventor: James H. Ackerman, Bethlehem,

N Y [56] References Cited [73] Assignee: Sterling Drug Inc., New York, NY. UNITED STATES PATENTS 969 T- 260 559 22 Filed: May 29, 1973 l [2]] Appl. No.: 364,290 Primary ExaminerHarry I. Moatz Attorney, Agent. or Firm-Thomas L. Johnson; B. Related U.S. Appllcatlon Data Woodrow Wyatt [60] Division of Ser. No. l8l,248, Sept. 16, l97l, Pat. No. 3.780,04l. which is a continuation-impart of Ser. No. 84l.604, July I4, 1969, Pat. No. 3.660.403, ABSTRACT which is a cominumicm-in-pan 0f 75,533 Cyclic imides and anilic acids of 2,4,6-triiodoanilines March 1968' abandoned bearing a substituted amino group in the 3-position are prepared by decarboxylation of the corresponding [30] Fore'gn Apphcmon Pnomy Data compounds bearing a carboxyl group in the 5-position.

Mar. l8, I969 Canada 046086 The products are useful as intermediates and as cholgcystographic agents. [52] U.S. Cl. 260/243 B; 260/244 R; 424/246;

4 Claims, No Drawings stituted amino group in the 3-position, and with intermediates and methods for the preparation of these compounds.

A preferred aspect of the invention resides in compounds of the formulas:

- N-CO-Y -COOR" wherein Y is a lower-alkylene group wherein Z or 3 carbon atoms separate the carbonyl groups, vinylene or a l,3-propylene group wherein the Z-carbon atom is replaced by O, S, S or S0 Y is a single bond, vinylene or an alkylene bridge having from one to eight carbon atoms or such a group interrupted by from one to three identical members selected from O, S, 80 and S0 said members, when more than one, being separated by at least two carbon atoms; R is (loweralkanoyl )NH, (lower-a lkanoyl )NHCH. (loweralkanoyl )N( lower-alkyl (lower-alkoxy-loweralkanoyl )NH, (lower-alkoxy-lower-alkanoyl )N( loweralkyl),

co Y: /N. co

HOOC-Y'-CONH, or HOOC-Y'-CO-N(lower-alkyl); R is hydrogen, Iower-alkyl, or hydroxy-lower-alkyl; and R" is hydrogen or lower-alkyl.

In the above formula A, Y stands for a lower-alkylene group wherein 2 or 3 carbon atoms separate the carbonyl groups and thus can be an ethylene or propylene group optionally substituted by lower-alkyl. The group Y can have from two to six carbon atoms and includes such groups as CH CH -CH CH CH CH C(CH;,) ,CH and the like, Y also stands for a 2-oxaor 2-thia-l ,3-propylene group having from 2 to 4 carbon atoms, for example. -CH OCH the like. The group Y in formula B is not limited to a two or three carbon bridge but represents a single bond or a divalent bridge, as hereinabove defined. having from one to eight carbons separating the carbonyl and carboxyl groups, optionally interrupted by from one to three identical members selected from O. S, SO and S0 The term interrupted means, of course. interposed between carbon atoms and not in a terminal position adjacent to the carbonyl groups.

When R in the above formulas A and B stands for (lower-alkanoyUNH, (lower-alkanoyl )NHCH (loweralkanoyl)-N( lower-alkyl (lower-alkoxy-loweralkanoyl)NH or (lower-alkoxy-lower-alkanoyl)N(lower-alkyl), the lower-alkanoyl group has from one to six carbon atoms thus including, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, caproyl, and the like.

When R stands for (Iower-alkanoyl)N(lower-alkyl), (lower-a1koxy-lower-alkanoyl )N( lower-alkyl or HOOC-Y'-CO-N(lower-alkyl), and/or R stands for lower-alkyl, and/or R" stands for lower-alkyl, the lower-alkyl group has from one to four carbon atoms, thus including, for example, methyl, ethyl, propyl, isopropyl, and butyl.

When R stands for (lower-alkoxy-loweralkanoyl)NH or (lower-alkoxy-lower-alkanoyl)N(lower-alkyl), the lower-alkoxy groups have from one to four carbon atoms and thus include, for example, methoxy, ethoxy, propoxy, isopropoxy. butoxy, and the like.

The compounds of the invention of formulas A and B above are prepared by decarboxylation of compounds of formulas C and D, respectively, as follows:

coon

N-/CO\Y I a N-CO-Y -coon" wherein Y, Y, R, R and R" have the same meanings given hereinabove. The decarboxylation is carried out by heating a compound of formula C or D, either in the free acid or salt form, in an organic solvent. A preferred method is heating the free acid or salt form, for example, the sodium salt in dimethylformamide at a temperature between about and C,

The intermediate carboxylic acids of formulas C and D are the subject of my copending application Ser. No. 808,653, filed Mar. 19, l969, now US. Pat. No. 3,609,147, a continuation-in-part of abandoned applications Ser. Nos. 550,6l4 and 715,558, filed May 17, I966, and Mar. 25, l968, respectively, and are prepared as described below.

The method of preparation of the compounds of formulas C and D varies according to the structure desired as follows:

I. Compounds of formula C where R is (loweralkanoyl )NHCH (loweralkano vl )Ni lower-alk l llower-alkoxydower-alkanoyl IN( lower-alkyl or HOOC-Y-CO-NHower-alkyl a. Using a dibasic acid anhydride: A compound of the formula COOH N'HQ

wherein R has the meaning given above under l and Q is hydrogen or lower-alkanoyl, is heated with an acid anhydride of the formula co I COOl-l 0 N NH COOH /CO\ H N KICl When Y is a lower-alkylene group, the reaction is prei erahly carried out in the presence ofa strong acid catalyst for example. sulfuric acid or phosphoric acid.

When the reaction is carried out with a compound of oyl group is lost and replaced by the cyclic imide group.

h. Using a succinyl or glutaryl chloride:

A compound of formula E where Q is hydrogen is heated with a compound of the formula CIOC-Y* COCl. where Y is a lower-alkylene group wherein Z or 3 carbon atoms separate the carbonyl groups. in an inert solvent.

2. Compounds of formula D where R is hydrogen.

a. Where Y is within the scope of Y. and R" is hydrogen:

These compounds can be prepared by alkaline h drolvsis of the corresponding compounds of formula C The reaction takes place in aqueous solution under mild conditions. at room temperature. Under these conditions the amide linkage to the 3-amino group is unaffected.

1). Where R is as given under method l l above:

These compounds can he prepared by reacting a compound of formula E where Q is hydrogen with a halfester half acid chloride. CI*CO-Y'*CO-OR". in an inert solvent, affording a compound of formula D where R" is lower-alkyl. Hydrolysis of the latter under mild alkaline conditions gives an anilic acid of formula D where R" is hydrogen.

3. Compounds of formulas C and D wherein R is i low er-alkanoyl JNH or llower-alkoxy-lower alkanovl )N H.

These compounds can he prepared from 3amino 5 nitrobenzoic acid according to the following flow sheet:

COOH

COOH

( ontinueil COOH H I I I I H N l N Y H N NHCO Y COOH (c, R H N) (D, R H N, R and R" a) Alkanoic Alkanoic Anhydride Anhydride COOK COOH I I I I (lower-a1kanoy1)NH N Y (lower-alkanoyl) NHCO-Y-COOH B-Amino-S-nitrobenzoic acid is reacted with an anhydride. O(COJ Y, to give the cyclic imide (F). The latter can either be hydrogenated under acid or neutral con ditions to give the amino cyclic imide (G) or hydro lyzed under basic conditions to give the corresponding nitro-anilic acid (H). The nitro-anilic acid in turn can be hydrogenated to the amino-anilic acid (J). lodin ation of the amino cyclic imide (G) affords a compound of formula C where R is H N, and iodination of the amino-anilic acid (J) gives a compound of formula D where R is H H and R is H. The primary amino groups can then, if desired. be acylated with a lower alkanoic acid anhydride or lower-alkoxy-loweralkanoic acid anhydride to give. respectively. a compound of formula C where R is (lower-alkanoyllNH or (lower-alkoxy-lower-alkanoyl)NH. or a compound of formula D where R is (lower-alkanoyl)NH or (loweralkoxy-lowenalkanoyl)NH and R is hydrogen.

4. Compounds of formulas C and D where the groups in the 3- and 5-positions are identical.

These are most conveniently prepared from 3.5- diamino-2,4.6triiodobenzoic acid. The latter is reacted with at least two equivalents of an anhydride, 0(- CO) Y, to afford a compound of formula C where R is Y(CO) N. which then can be hydrolyzed to a compound of formula D where R is HOOCYCONH and R and R" are H. The starting material can also consist of a 3-lower-alkanolyamino-S-amino-2.4.6-triiodobenzoic acid or a 3,5bis(lower-alkanoylaminolbenzoic acid. In the reaction with the anhydride the lower-alkanoyl groups are replaced by cyclic imide groups. Alternatively, a method analogous to method 2(b) above can be used. i.e., reacting 3,5-diamino 2.4.6-triiodobenzoic acid with a half ester half acid chloride Cl-CO-YCO-OR", affording a compound of formula 8 where R is R"OCOYCONH. R is H and R is lower-alkyl.

5. Compounds of formula D wherein R is lower-alkyl or hydroxy-lowcnalkyl.

These compounds can be prepared by N-alkylation of the corresponding compounds where R is hydrogen. The alkylation is effected by the action ofa lower-alkyl or hydroxy-lower-alkyl halide. sulfate. alkylsulfonate or arylsulfonate in the presence of aqueous alkali. if the starting material is a compound of formula D where R is (lowcr-alkanoyllNH or HOOC-Y-CO-NH, ulkyla tion occurs on both nitrogens simultaneously.

The compounds of the invention where Y and/or Y are alkylene groups interrupted by S0 or SO can alternatively be prepared by oxidation of the corresponding sulfide (S) compounds with a period or hydrogen peroxide. The reaction takes place at room temperature in an inert organic solvent.

Alternatively, the compounds of formulas A and B can be prepared from compounds of the formula:

wherein R is H N, (lower-alkanoyllNH, (loweralkanoyl )NHCH (lower-alkanoyl )N( lower-alkyl (lower-alkoxyJower'alkanoyl )N( lower-alkyl,

or HOOCY-CO-N( lower-alkyl where Y has the meaning given hereinabove. and Q is hydrogen or lower-alkanoyl. by formation of the cyclic imides and anilic acids by methods analogous to'those described above for the preparation of compounds of formulas C and D. The compounds of formula K are in turn pre pared by decarboxylation ofthe compounds of formula E or by other procedures known in the art as illustrated by the specific examples hereinbelow.

The structures of the compounds of the invention were determined by the modes of synthesis. by elementary analysis and by neutral equivalent determinations. The course of the reactions was followed by thin-lay er chromatography.

Those compounds of the invention which are carboxylic acids can be obtained in the form of salts derived from inorganic bases or organic amines. Preferred salts are those which are pharmaceutically acceptable, for example, the sodium, magnesium. calcium and N- mcthylglucamine salts; although all salts are useful either as characterizing derivatives or as intermediates in the purification of the acids.

The compounds of the invention having the formula A wherein R is HOOC-Y'CONH or HOOCY'CON(lower alkyl). and the compounds of the invention having the formula B are useful as X-ray contrast media for visualization of the gallbladder (chloecystography). The compounds have intravenous toxicity (approximate LD values) in the range between 600 and 7500 mg/kg in mice. The compounds of lesser toxicity, LD 1500 mg./l g. or greater. are primarily useful, in the form of their watersolublc. pharmaceutically acceptable salts. as intravenous cholecystographic agents. The compounds having LD values less than about 1500 mg./kg. are primarily useful. either in the free acid or salt form. as oral cholecystographic agents.

The actual quantitative determination of toxicity and radiopaquc effectiveness for a particular compound is readily determined by standard test procedures by technicians trained in pharmacological test procedures, without the need for any extensive experimentation The compounds were tested for their intravenous cholecystographic efficacy by standard procedure as follows. The test compound was injected intravenously in the form of an aqueous solution of the sodium or N-methylglucamine salt to cats. Each cat was X-rayed at selected time intervals and the roentgenograms examined and evaluated. The density of the gallbladder shadows was interpreted in accordance with a numercial scoring plan designated as the Cholecystographic Index (CI a measure of the efficiency of the test compound. viz.: (none). 1 (poor). 2 (fair), 3 (good), 4 (excellent) [see 1. O. Hoppe. J. Am. Pharm. Assoc, Sci. Ed. 48. 36879 (l959)].

In testing for oral cholecystography. the test compound was administered orally in capsules to each of five cats. About eighteen hours later, each cat was X-rayed and the roentgenograms were examined. The density of the gallbladder shadow evoked by the test compound in each cat was interpreted in accordance with the above numerical scoring plan and the Average Cholecystographic Index (ACI) determined.

The compounds of the invention. upon testing for cholecystographic efiectiveness in cats at a dose of 100 mg./kg.. were found to produce gallbladder shadows having a Cholecystographic Index of 3.04.0 either by oral or by intravenous administration.

The compounds of the invention are prepared for cholecystographic use by dissolving a pharmaceutically acceptable salt form in sterile aqueous medium suitable for intravenous injection; or in capsule or in tablet form with conventional excipients for oral administration.

The compounds of formula A, wherein R is (loweralkanoyl )NH, (lower-alkanoyl )NHCH (loweralkanoyl )N( lower-alkyl (lower-alkoxy-loweralkanoyl NH. (lower-a1koxy-lower-alkanoyl)N(loweralkyl) or are useful as intermediates. by hydrolytic cleavage. for the preparation of compounds of formula B.

The following examples will further illustrate the invention.

EXAMPLE 1 a. 3,5-bis(Glutarimido)-2.4.6-triiodobenzoic Acid [C;

R is (CHZMCOMN. Y is CH CH CH- l was prepared from 265 g. of 3.5diamino-2.4.6-triiodobenzoic acid. 400 g. of glutaric anhydride and 18 ml. of concentrated sulfuric acid. heated and stirred for 17 hours. The product was recrystallized from dimethyl sulfoxide. adding water to induce precipitation, and was obtained as a light gray solid with one mole of dimethyl sulfoxide of crystallization. m.p. above 300C. A sample of the acid was converted to its sodium salt form. m.p. 28829lC. (dec.) when recrystallized from water.

b. N,N-(2.4.o-Triiodo-m-phenylene)diglutarimide [A;

R is (CH );,(CO) N. Y is CH CH CH A mixture of 89.10 g. of sodium 3,5-bis(- glutarimido)-2.4.6-triiodobenzoate and 400 ml. of dimethylformamide was warmed at C. for 20 minutes to effect solution. and then heated at reflux temperature (l35C.) for 4 hours. The solution was cooled. and the solid product collected, washed with dimethylformamide and acetone, and dried to constant weight (35.18 g.). An additional 41.75 g. of product was obtained by diluting the filtrate with water. The combined product was recrystallized from acetic acid. using activated charcoal for decolorizing purposes, to give N.N-(2.4,fi-triiodo-m-phenylene)diglutarimide. colorless prisms, mp above 300C.

N,N-( 2.4,6-Triiodo-m-p henylene )diglutarimide can also be prepared by reacting 3-amino-2,4.6-triiodoaniline (K; R is H N, Q is H), 3-amino-2,4,6-triiodoacetanilide (K; R is H N. Q is COCH or 3- acetamido-Z .4.6-triiodoacetanilide (K; R is CH CONH, Q is COCH with glutaric anhydride according to the procedure of Example l. part (a).

EXAMPLE 2 3-Glutarimido-5-(N-methylacetamido)-2,4,6-triiodobenzoic Acid [C', R is CH CON(CH Y is CH CH CH I. A mixture of l l7.2 g. of 3-amino-5-(N- methylacetamido)-2,4.6-triiodobenzoic acid and 182 g. of glutaric anhydride was heated with stirring on a steam bath. Concentrated sulfuric acid (10 ml.) was added. and heating and stirring were continued for seven hours. The reaction mixture was added to 700 ml. of water, and the solid product was collected by filtration and recrystallized from acetic acid. The re sulting 3-glutarimido-5-( N-methylacetamido )-2,4,6- triiodobenzoic acid was converted to its sodium salt form as follows: the free acid was slurried with 40 ml. of methanol and a lN solution of sodium hydroxide in methanol was added with trituration until the solid had dissolved. The sodium salt was precipitated out with ether, and the resulting gum was triturated with ether and dissolved in methanol. The latter solution was decolorized with activated charcoal and the product reprecipitated with ether. The product was dissolved in water and the solution filtered and concentrated in vacuo. The residue was dried in vacuo to give the sodium salt of 3-glutarimido-5-(N-methylacetamido)- 2,4,6-triiodobenzoic acid as a pale pink solid, mp. 200204C. (dec.

b. N-[2,4.6-Triiodo-3-(N-methylacetamido)phenyllglutarimide [A; R is CH -,CON(CH;,). Y is CH CH CH can be prepared by decarboxylation of sodium 3- glutarimido-5-( N-methylacetamido )-2,4,6-triiodobenzoate according to the procedure of Example [(b); or by decarboxylation of 3-acetamido-5-( N- methylacetamido)-".4,6-triiodobenzoic acid followed by reacting the resulting 3-( N-methylacetamido)-2,4.6-

9 triiodoacetanilide [K; R is CH CON(CH.1% Q is COCH with glutaric anhydride.

By replacing the 3-amino-5-(N-methylacetamidol- 2,4,6-triiodobenzoic acid in the foregoing preparation by a molar equivalent of 3-amino-5-(N- butylacetamido)-2,4,6-triiodobenzoic acid, 3amino-5- (N-methylpropionamido )-2.4,6-triidobenzoic acid, 3-amino- N-methylcaproylamino )-2,4,6-triiodobenzoic acid, 3-amino-5-(N,N'dimethylcarbamoyl)-2,4,6- triiodobenzoic acid, or 3-amino-5-(N-methyl-2- methoxyacetamido)-2.4,6-triiodobenzoic acid, there can be obtained, respectively, 3-glutarimido-5-(N butylacetamido)-2,4,6-triiodobenzoic acid [C; R is CH CON(C,H Y is CH CH CH 3-glutarimido-5- (N-methy lpropionamido )-2 ,4,6-triiodobenzoic acid [C; R is CH CH CON(CH Y is CH CH CH 3- glutarimido-5-(N-methylcaproylamimo)-2,4,6-triiodobenzoic acid [C; R is CH (CH CON(CH Y is CH CH- CH 3-glutarimido-5-(N,N-dimethylcarbamoyl 2,4,6-triiodobe nzoic acid [C R is (CH NCO, Y is CH- CH CH or 3-glutarimido-5- (N-methy l-2-methoxyacetamido )-2,4,6-triiodobenzoic acid [C; R is CH OCH CON(CH Y is CH CH CH which in turn can be decarboxylated to give, respectively, N-[2,4,6-triiodo-3-( N-butylacetamido )phenyllglutarimide [A; R is CH C0N(C H Y is CH CH CH l, N-[2,4,6-triiodo-3-(N-methylpropionamido)-phenyl]glutarimide [A; R is CH CH CON(CH Y is CH CH CH N-[2,4,6-triiodo-3-(N-methylcaproylamino)phenyllglutarimide [A; R is CH (CH CON(CH Y is CH CH CH N-l 2,4,6-triiodo-3-(N,N-dimethylcarbamoyl)phenyl]- glutarimide [A', R is (CHQ NCO, Y is CH CH CH- or N-[2,4,6-triiodo-3-(N-methylmethoxyacetamido)- phenyl]glutarimide [A', R is CH OCH CON(CH Y is CH CH CH EXAMPLE 3 3-Succinimido-5-( N-methylacetamido )-2,4 ,6-triiodobenzoic Acid [C; R is CH CON(CH Y is CH CH was prepared from 87.9 g. of 3-amino-5-(N methylacetamido)-2,4,6-triiodobenz0ic acid, 120 g. of succinic anhydride and 6 ml. of sulfuric acid according to the procedure of Example 2, except that a reaction temperature of ll40C. was used. The reaction was essentially complete after 30 minutes heating time. The compound was isolated in the form of its sodium salt, pale yellow solid, mp. 220-222C. (dec.). b. N-[2 ,4,6-Triiodo-3-( N-methylacetamido )pheny11- succinimide [A; R is CH CON(CH Y is CH- CH can be prepared by heating sodium 3-succinimido-5- (N-methylacetamido)-2,4,6-triiodobenzoate in dimethylformamide by the method described in Example (b).

EXAMPLE 4 can be prepared by heating sodium 3-succinimido-5- N-methylacetamido)2,4,6-triiodoben2oate in dimethylformamide by the method described in Example The following compounds were prepared following the procedure of Example 1 from the appropriate 3- amino-5-R-2,4,6-triiodobenzoic acid and acid anhydride:

Example 5: 3-( 3,3-Dimethylglutarimido )-5-( N- methylacetamido)-2,4,6-triiodobenzoic Acid [C; R is CH;,CON(CH Y is CH C(CH CH pale tan solid, mp 274278C. (dec.) (from acetic acid); sodium salt form, pale yellow solid, mp.

235245C. (dec.).

Example 6: 3-Glutarimido-S(N-methylacetamido)- 2.4,6-triiodobenzoic Acid [C; R is CH -;CON(C H Y is CH CH CH sodium salt form, m.p. above 220C.

Example 7: 3-(Methylsuccinimido)-5-(N- methylacetamido)-2,4,6-triiodobenzoic Acid [C; R is CH CON(CH Y is CH(CH )CH CH m.p. 285287C. (from acetic acid); sodium salt form,

m.p. above 245C. (dec.).

Example 8: 3-(Digylcolimido)-5-N-methylacetamido)- 2,4,6-triiod0benzoic Acid [C; R is CH CON(CH Y is CH OCH sodium salt form, m.p. 250255C. No sulfuric acid was used in this preparation.

Example 9: 3-( 3,5Dioxothiomorpholino )-5-( N- methylacetamido)-2,4,6-triiodobenzoic Acid [C; R is CH CON(CH Y is CH SCH sodium salt form, beige solid, mp. 250260C. (dec.

N0 sulfuric acid was used in this preparation.

The compounds of Examples 5, 6 and 7 can be decarboxylated by the method of Example l(b) to produce, respectively, N-[ 2,4,6-triiodo-3-( N-methylacetamido phenyl]-3,3-dimethylglutarimide [A; R is CH3CON(CH3). Y is CH C(CH CH N-[2,4,6-triiodo-3-(N-ethylacetamido)phenyllglutarimide [A; R is CH CON(C H Y is CH CH CH and N [2,4,6 trii- 0do-3-( N-methylacetamido )phenyUmethylsuccinimide [A; R is CH ,CON(CH Y is CH(CH )CH CH The compounds of Examples 8 and 9 were decarboxylated by heating the free acid forms in dimethylformamide, minutes at reflux temperature. There was obtained, respectively, N-l 2,4,6-triiodo-3-( N- methylacetamido)phenyl]diglycolimide [A; R is CH CON(CH Y is CH OCH m.p. 264266C. (from dimethylformamide and 4[2,4,6-triiodo-3-(N- methylacetamido )phenyl 3 ,S-thiamorpholinedione (A; R is CH CON(CH Y is CH ScHzl. beige solid, mp. 283285C. (from acetic acid). The latter two compounds were also prepared by heating together at l20l50C. equal weights of 2,4,6-triiodo-3-(N- methylacetamidoJaniline and diglycolic anhydride or thiodiacetic anhydride, respectively.

3-( 3,5-Dioxothoimorpholino )-5-[N- methylacetamido)-2,4,6-triiodobenzoic acid can be oxidized with m-chloroperbenzoic acid in dimethylformamide solution to give 3-(3,5,S-trioxothiomorpholino)-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid [C; R is CH CON(CH Y is CH SOCH and 3-( 3 .5 ,S,S-tetraoxothiomorpholino )-5-( N methylacetamido)-2,4,6-triiodobenzoic acid [C; R is CH CON(CH Y is CH SO CH which can be de carboxylated according to the procedure of Example l(b) to give 4-[2,4,6-triiodo-3-(N-methylacetamido)- phenyl]-3,5,S-trioxothiomorpholine [A; R is CH CON(CH Y is CH SOCH and 4-[2,4,6-triiodo- 3-(N-methylacetamido)phenyl]-3,5,S,S-tetraoxothill omorpholine [A; R is CH COMCHQ. Y is CH SO CHQ. respectively.

EXAMPLE a. 3-Carboxy-5 N-methylacetamido ,4,6-triiodoglutaranilic Acid [D R is CH COMCHU. R and R" are H. Y is CH CH CH A mixture of 58.6 g. of 3-amino-5 (N methylacetamido)-2.4.6-triiodobenzoic acid. 74 g. of glutaric anhydride and 8 ml, of concentrated sulfuric acid was heated on a steam bath for five hours. The reaction mixture was poured into water and the solid product collected by filtration. The product. consisting of 3-glutarimido-5-( N-methylacetamido )l.4.6-triiodobenzoic acid (Example 2) was dissolved in excess dilute aqueous sodium hydroxide. and the solution warmed for thirty minutes. then cooled and 3N hydrochloride acid added slowly until precipitation was complete. The solid product was recrystallized and rectys h EXAMPLE 1 l a. 3 -Carboxy5 N-methylacetamido )-2 ,4,6'-triiodosuccinanilic Acid [D; R is CH CoMCH R and R are H. Y is CH CH was prepared from 34.3 g. of 3-amino-5-(N- methylacetamido)-2,4.o-triiodobenzoic acid. 82 g. of

succinic anhydride and 5 ml. of concentrated sulfuric acid. followed by alkaline hydrolysis of the resulting 3-succinimido-5-( N-methylaeetamido 2,4.6-triiodobenzoic acid. according to the method described in Example 10. The product was recrystallized from dilute ethanol and from a methanol-acetonitrile mixture and further purified by converting it to the diammonium salt by means of ammonium hydroxide in methanol. and then acidifying an aqueous solution of the ammonium salt to regenerate the free acid. There was thus obtained 3 carboxy-5 N-methylaeetamido )-2 ,4,6- triiodosuccinanilic acid. m.p. 27S.O276.0C. (dec.).

b. 2,4,6Triiodo-3 N-methylacetamido )suc cinanilic Acid [8; R is CH CON(CH R and R are H. Y is CH CH L colorless prisms. m.p. 2092l lC.. was prepared from 37.8] g. of disodium 3 -carboxy-5 N- methylacetamidoj-2.4,6-triiodosuccinanilate in lUU ml. of dimcthylformamide. 40 minutes at reflux. The

mixture was acidified with hydrochloric acid and the product collected and recrystallized from acetone.

Similarly. by warming in dilute aqueous sodium hydroxide. 3-glutarimido-5-(Nbutylacetamidov2.41 triiodobenzoic acid. 3-glutarimido-5-lN-rncthylpropionamido)-2.4.6-triiodobenzoic acid. 3-glutarimido- 5 t N-methylcaproylamino )-2.4,6-triiodobenzoic acid. or 3-glutarimido-54N-methyl-2-methoxyacetamido,l- 2.4.6triiodobenzoic acid can be hydrolyzed. respec tively. to 3carboxy-5-(N butylacetamido)-2,-1,6-

triiodoglutaranilie acid [D; R is CH CQNtC H R methylpropionilihldo)-2,4.6-triiodoglutaranilic acid [D; R is CH CH CONCH R and R are H. Y is CHQCHQCH: 3-carboxy-5 '-i N'mcthylcaproylaminorl.4.odriiodoglutaranilic acid [D; R is CH (CH CONt(H R and R are H. Y is CH CH CH or 3-carboxy-5-(N-methyl-2methoxyacetamido)-2.4'.6-triiodoglutaranilic acid [[1 R is CH oCH CoNtCi-l R and R" are H. Y is CH CH CH l; and in turn decarboxylated to give. respectively, 3 N-butylacetamido )-2 .4,6-triiodoglutaranilic acid [B; R is CH CON(C H 9) R and R" are H. Y is CH CH CHZL 3-(N-methylpropionamido)-2,4,6triiodoglutaranilic acid [8; R is CH CH CON(CH R and R are H. Y is CH CH CH2 l, 3 N-methylcaproylamino l-Z .4,6- triiodoglutaranilic acid [B; R is CH;;lCH- ).,CON(CH R and R are H. Y is CH CH CH or 3( Nmethyl- Z-methoxyacetamido)-2.4,6-triiodoglutaranilic acid [8; R is CH OCH CONtCH R and R are H. Y is CH CH CH 3-C'.irbox v-5 N-methylacetamido J-Z ,4,6-triiodoglutaranilic acid can also be prepared by heating 3-amino-5-( N-methylacetamido -2.4,6-triiodobenzoic acid with 4-carbomethoxybutyryl chloride (CH O- COCH CH CH COCl in dioxane solution, followed by hydrolysis of the resulting methyl 3-carboxy-5-(N- methylacetamido J-2 ,4,6 -triiodoglutaranilate by heating it with potassium carbonate in methanol solutton.

Similarly. 3-amino-5-( N-methylacetamido )2.4,6 triiodobenzoic acid can be caused to react with Cl- COCH CH CH CH COOCH ClCOCH C- H OCH CH COOCH ClCOCH CH OCH C- H OCH CH OCH CH COOCH, or Cl- COCH SCH CH CH CH SCILCOOCH to give. respectively. the following compounds: [D; R is CH -;CON(CH;,), R is H. R" is CH Y is CH CH CH CH [D; R is CH CON(CH;,). R is H. R is CH Y is cn cn oca cun; [D'. R is CH CON(CH R is H. R is CH Y is CH CH- OCH- CH OCH CH OCH CH i or [D1 R is CH.-,CON(CH;,). R is H. R" is CH;,. Y is CH SCH CH CH CH SCH I. These can be hydrolyzed to the corresponding dibasic acids where R is hydrogen and decarboxylated to give. respectively. the fol lowing compounds: [8; R is CH ,CON(CH;;). R and R" are H. Y is CHQCHQCHQCHQ]; [8; R is CH.-;CON(CH;,). R and R are H. Y is CH CH OCH CH [8; R is CH COMCHM. R and R are H. Y is CH CH OCH CH OCH CH OCH CH i or [B; R is CH CON(CH R and R are H. Y is CH SCH CH CH CH SCH The starting half-ester half-acid chlorides are a known class of compounds readily prepared by partial hydrolysis of the corresponding diesters followed by reaction of the resulting half-esters with thionyl chloride.

In the same manner. 3.S-diamino-2.4.6-triiod0ben- Zoic acid can be caused to react with Cl- COCH CH CH CH COOCH to give [D; R is CH O- COCH CHgCHgCHgCONH. R is H, R is CH Y is CH- CH CH CH which can be hydrolyzed to give [D; R is HOCOCH CH CH CH CONH. R and R" are H. Y is CH CH CH CH:]. and the latter decarboxylated to give [8; R is HOCOCH CH CH CH CONH. R and R are H. Y is CH CH CH CH l.

EXAMPLE 12 a. 3-[2-Carboxymethylsulfonyl)acetamido1-2.4.6-triiodo-5-(N-methylacetamido)benzoic Acid [D; R is CH;;CON(CH R and R are H. Y is CH SO CH A solution of 26.1 g. of 3-amino-5-(N- methylacetamido )-2,4.6-triiodobenzoic acid in 300 ml. of dioxane was distilled until about 60 ml. of dioxane was removed in order to eliminate possible traces of water. Sulfonyldiacetyl chloride (ClCOCHi SO CH- COCI) (5.85 g.) was then added. and the mixture was stirred and refluxed for about five days. The reaction mixture was concentrated in vacuo to remove the solvent. and the residue was dissolved in dilute sodium hydroxide to give a solution of the sodium salt of the product. The basic solution was made weakly acid. which did not cause precipitation of the acid form of the product. treated with activated charcoal at 60C. and filtered. The filtrate was acidified with 3N hydrochloric acid and the precipitated product collected. The acid product was purified by dissolving it in ammonium hydroxide solution and reacidifying the resulting ammonium salt solution. The acid product was recrystallized from aqueous dimethylformamide to give 3-[2- tcarboxymcthylsulfonyl )acetamido1-2.4.6-triiodo-5- tNmethylacetamido)benzoic acid. m.p. above 300C. b. {N-[ 2 .4.6Triiodo-3-( N-methylacetamido )phenyl}- carbamoylmethylsulfonyl)acetic Acid [8; R- is CH CON(CH R and R" are H. Y is CH SO CH can be prepared by decarboxylation of 3-[2-(carboxymethylsu lfonyl )acetamido ]-2.4,6-triiodo-5-( N- methylacetamido)benzoic acid according to the procedure of Example 1(b). The product is the same as that described in Example below.

By replacing the sulfonyldiacetyl chloride in the foregoing preparation by sulfoxydiacetyl chloride (ClCOCH- |SOCH COCl) there can be obtained 3-{ 2-( carboxymcthylsulfoxy )acetamido] 2.4.6-triiodo- 5-(N-methylacetamido)benzoic acid [D; R is CH;,CON(CH R and R" are H. Y is CH SOCH which can be decarboxylated to give {N[2,4,6-triiodo- 3-(N-methylacetamido)phenyl]carbamoylmethylsulfoxy}acetic acid {8; R is CH CON(CH R and R" are H. Y is CH SOCH The following compounds can be prepared either by mild alkaline hydrolysis of the corresponding cyclic imides. or directly from the appropriate 3-amino-5R- 2.4.6-triiodobenzoic acid without isolation of the intermediate cyclic imide, followed by decarboxylation of the resulting anilic acid. as described above in Examples ll) and 11.

Example 13: (a) 3-Carboxy-2,4,6'-triiodo-3-methyl- 5(N-methylacetamido)glutaranilic Acid [D; R is CH CON(CH R' and R are H. Y is CH CH(CH;,)CH- l.

colorless crystals, mp. 256259C.(dec.).

b. 2.4.6-Triiodo-3-methyl-3-(N-methylacetamido)- glutaranilic Acid [8; R is CH CON(CH R and R are H. Y is CH CH(CH )CH pale tan crystals from aqueous acetic acid, mp.

l89l93C.; sodium salt form, beige powder from methanol-ether, mp. 202204C.

Example 14: (a) 3,5bis(4-Carboxybutyramido)-2.4.6-

triiodobenzoic Acid [D'. R is HOOC(CH );.CONH, R and R" are H. Y' is CH CH CH colorless solid. mp. 251253C. (from acetic acid).

b. N.N( 2.4.6-Triiodo-m-phenylene )diglutaramic Acid [8; R is HOOC(CH CONH. R and R are H. Y is CH CH CH colorless prisms from acetic acid. mp 278-279C [prepared by hydrolysis of N,N- (2.4.o-triiodo-m phenylene )diglutarimide (Example 1b} with sodium hydroxide in acetone solution 2 hours at reflux].

b. 2,4,6'-Triiodo-3.3-dimethyl-3 N- methylacetamido)glutaranilic Acid [8; R is CH COMCH R and R" are H. Y is [0 tan powder, mp. l32l34C.

Example 16: (a) 3'-Carboxy-5-[N-ethylacetamido)- 2,4,6'-triiodoglutaranilic Acid [D; R is CH CON(C H R and R" are H, Y is CH CH CH colorless solid, mp. 250C. (dec.

b. 2,4,6-Triiodo-3 N-ethylacctamido )glutaranilic Acid [8; R is CH CON(C H;,). R and R" are H. Y is CH CH CH Example 17: (a) 3'-Carboxy-2,4,6-triiodo-3-methyl- 5-(N-methylacetamido)succinanilic Acid [D; R is CH CON(CH3J, R and R are H. Y is l sl ul light orange solid. mp. 262264C. (dec.).

b. 2,4,6-Triiodo-3-methyl-3 N-methylacetamido J- succinanilic Acid [8; R is CH CON(CH;;). R and R are H. Y is CH(CH;,)CH

Example 18: (a) 3-Carboxy-2',4,6'-triiodo-5-(N- methylacetamido)digylcolanilic Acid [D'. R is CH;,CON(CH R and R are H. Y is CH OCH I. disodium salt form. light tan solid. mp. 24526(.)C. (dec.).

b. 2.4,6"Triiodo-3 N-methylacetamido )digylcolanilic Acid [8; R is CH CON(CH;il. R and R are H, Y is CH OCH colorless solid. mp. l33C.

Example 19: (a) 3 [2-(Carboxymethylthio )acetamido]-2.4.6-triiodo-5-( N-methylacetamido benzoic Acid [D; R is CH=,CON(CH.-;l. R and R" are H. Y is CH SCH beige solid, mp. l65l70C.

b. {N-[ 2.4.6-Triiodo-3-( N-methylacetamido )phenyl carbamoylmcthylthiolacetic Acid [8; R is CH CON(CH R and R are H, Y is CH SCH l.

EXAM PLE 2O lN-[2,4.6Triiodo-3ekN-mcthylacetamido )phenyl learlN-[2.4,6-Triiodo-3-( N-methylacetamido )phenyl carbamoylmethylthio}acetic acid (derived by hydrolysis of 25.0 g. of 4-[ 2'.4,6-triiodo-3-( N- methylacetamido)phenyl1-3.S-thiamorpholinedione) was dissolved in ml. of glacial acetic acid at 40C. Hydrogen peroxide (72 ml. 30%) was added. After 5 minutes the mixture was concentrated to a volume of 75 ml. and 400 ml. of water added. The product which separated was crystallized by stirring the mixture in ice. and was collected and dried to give {N[2.4.6-triiodo- 3-( Nmethylacetamido )phenyl lcarbamoylmethylsulfonyl}acetic acid. m.p. l48l50C. (dec.).

EXAMPLE 21 a. 3-Succinimido-S-nitrobenzoic Acid [F; Y is CH CH J was prepared by heating 3amino-5- nitrobenzoic acid with succinic anhydride in the presence of sulfuric acid. It had the m.p. 2o2-2o8C. when recrystallized from aqueous dimethylformamide.

b. 3'-Carboxy-5nitrosuccinanilic Acid [H: Y is CH cH- l was prepared by treating 3-succinimido-5- nitrobenzoic acid with warm dilute aqueous sodium hydroxide, and had the m.p. 220-22lC c. 3'-Carboxy-5'-aminosuceinanilic Acid [1; Y is C H- CH 3'Carboxy-5-nitrosuccinanilic acid (83.5 g.) and 50 ml. of concentrated ammonium hydroxide in I ml. of

water were added to a heated solution of 540 g. of

ferrous sulfate heptahydrate in 900 ml. of water. Concentrated ammonium hydroxide (100 ml.) was then added during minutes in 50 ml. portions. After minutes of heating on a steam bath. the reaction mixture was filtered and made acid to pH 3.5. The product was collected and dried in vacuo over phosphorus pentoxide to give 57.5 g. of 3-carboxy-5'-aminosuceinanilic acid, mp. 194C. (dec).

d. 3 Carboxy-S -amino 2 ,4,6'triiodosuccinanilic Acid [D; R is NH R and R" are H, Y is CH CH I. Potassium iododichloride (335 m]. 2.23N in water),

was added over a period of minutes to a stirred suspension of 57.3 g. of 3'-carboxy-5-aminosuccinanilic acid in 435 ml. of water. The solid product was collected by filtration and recrystallized from water and from aqueous dimethylformamide. The product was purified by converting it to the diammonium salt and then to the disodium salt, m.p. 222225C. tdec.) The latter was acidified to produce the free acid form of 3'-carboxy-5'-amino-2',4',6'-triiodosuccinanilic acid. cream colored solid. mp. l56.2-l72.2C. (dec).

3'-Carboxy-5-amino-2,4',6-triiodosuccinanilic acid can be aeylated with acetic anhydride, using a few drops of perchloric acid as a catalyst to obtain 3-carboxy-5'-acetamido-2,4',6'-triiodosuccinanilic acid [D;

R is CH CONl-l. R and R" are H. Y' is CH CH which can be decarboxylated according to the method of Example l(b) to give 2,4,6'-triiodo-3'- acetamidosuccinanilic acid [B: R is CH CONH, R' and R" are H. Y is CH- C'H- EXAMPLE 22 a. 3-Glutarimido-S-nitrobenzoic Acid [F; Y is CH CH CH was prepared by heating a mixture of 18.2 g. of 3- amino-S-nitrobenzoic acid, 45.6 g. of glutaric anhydride and 0.5 ml. of concentrated sulfuric acid on a steam bath for 2 hours. The product was isolated and recrystallized from aqueous dimethylformamide to give 3-glutarimido-5-nitrobenzoic acid, pale yellow prisms,

m.p. above 300C.

b. 3-Glutarimido-5-aminobenzoic Acid CH CH- CH can be prepared by reduction of 3-glutarimido-5- nitrobenzoic acid. The reduction can be carried out catalytically (platinum or nickel catalyst) under neutral or acidic conditions.

0. 3-Glutarimido 5-amino-2,4,6-triiodobenzoic Acid [C; R is HgN, Y is CH CH CH can be prepared by iodination of 3-glutarimido-5- aminobenzoic acid with potassium iododichloride according to the procedure described in Example 2 l part d. 3-Glutarimido-S-acetamido-2.4,6-triiodobenzoic Acid [C1 R is CH CONH. Y is CH- CH CH can be prepared by acetylation of 3-glutarimido-5- amino-2,4.6-triiodobenzoic acid with acetic anhydride,

using a few drops of perchloric acid as a catalyst.

[G; Y is e. 2',4,6'-Triiodo-3'-acetamidoglutaranilic Acid [8; R

is CH CONH, R and R" are H, Y is CH CH CH l can be prepared by hydrolysis and decarboxylation of 3-glutarimido-5-acetamido-2.4,6-triiodobenzoic acid. Alternatively, 3-glutarimido-5-amino-2,4,6-triiodobenzoic acid can be converted by mild hydrolysis to 3'- amino-S'-carboxy-2',4',6'triiodoglutaranilic acid, the latter decarboxylated to give 3'-amino-2,4',6'-triiodoglutaranilic acid, m.p. 225228C., which is then acetylated to give 2',4',6-triiodo-3'-acetamidoglutaranilic acid.

EXAMPLE 23 a. 3'-Carboxy-5'-amino-2,4',6'-triiodo-N-methylglutaranilic Acid [D; R is H N, R is CH R" is H, Y is CH CH CH To a solution of 26.0 g. of 3'-carboxy-5'-amino-2',- 4,6-triiodoglutaranilic acid [prepared by hydrolysis of 3-glutarimido-5-amino-2,4,o-triiodobenzoic acid (Example 22c)] in lOU ml. of 10% aqueous sodium hydroxide cooled in an ice bath was added 8 ml. of dimethyl sulfate in acetone. After 3 hours of stirring an additional l5 ml. of 10% sodium hydroxide and 2 ml. of dimethyl sulfate were added and the mixture stirred 3 hours longer. The reaction mixture was acidified, and the product collected and recrystallized from acetic acid to give 3'-carboxy-5'-amino-2,4',6'-triiodo-N- methylglutaranilic acid, pale gray crystals, m.p. 2l8220C. (dec.).

b. 3 -Carboxy-5 '-gl utarimido-2 ,4 ,6 '-triiodo-N- methylglutaranilic Acid [C; R is HOOC(CH -,CON(CH;,), Y is CH CH CH was prepared from 3'-carboxy-5amino-2,4',6'-triiodo-N-methylglutaranilic acid and glutaric anhydride according to the procedure of Example 1 The free acid was obtained as a colorless solid, mp. l60l6lC. when recrystallized from acetic acid, and the disodium salt form as a beige solid. mp. 252255C.

c. 3'-Glutarimido-2,4,6'-triiodo-N-methylglutaranilic Acid [A; R is HOOC(CH- CON(CH Y is CH CH CH was prepared from 29.65 g. of the disodium salt of 3-carboxy-5 '-glutarimido-2,4,6'-triiodo-N-methylglutaranilic acid in ml. of dimethylformamide, 30

minutes at reflux. The free acid product was obtained in the form of a mauve powder, m.p. 256-257C.; sodium salt form. mauve powder, m.p. 24l245C.

EXAMPLE 24 a. 3 '-Carboxy-5 N-methylacetamido)-2 ,4 ',6'-triiodo-N-methylglutaranilic Acid [D; R is CH CON(CH3). R is CH R" is H. Y is CH CH CH was prepared from 16.42 g. of the disodium salt of 3 "carboxy-S N-mcthylacetamido )-2 ',4,6triiodo- N-methylglutaranilic acid in 40 ml. of dimethylformamide, 30 minutes at reflux. The free acid product was recrystallized from aqueous acetic acid and obtained as pale cream-colored crystals, m.p. 90-l(lUC.; sodium salt form, m.p. l73l75C.

EXAMPLE a. 3'-Carboxy-5-(N-methylacetamido)-2,4,6'-triiodo-N-ethylglutaranilic Acid [D; R is CH CON(CH R is C H R" is H, Y is was prepared from 44.1 g. of the disodium salt of 3'- carboxy-S N-methylacetamido )-2,4 ,6-triiodo-N- ethylglutaranilic acid in 107 ml. ofdimethylformamide. 45 minutes at reflux. The product had the m.p. l l2-l 125C. when recrystallized from aqueous acetic acid.

3 -Carboxy-5 -(N-methylacetamido )-2,4,6-triiodoglutaranilic acid can similarly be alkylated with n-butyl iodide or 2-hydroxyethyl bromide to give 3- carboxy-S N-methylacetamido )-2,4 ,6-triiodo-N- butylglutaranilic acid [D; R is CH CON(CH R is C4Hg, R" is H, Y is CH CH CH or 3-carboxy-5- (N-methylacetamido )-2 ,4,6-triiodo-N( 2-hydroxyethyl)glutaranilic acid [D', R is CH CON(CH R is HOCH CH R is H, Y is CH CH CH which in turn can be decarboxylated to give, respectively, 2',4,6- triiodo-3 N-methylacetamido )-N-butylglutaranilic acid [8; R is CH CON(CH R is C H R" is H, Y is CH- CH CH or 2',4',6-triiodo-3-(N- methylacetamido)-N-( Z-hydroxyethyl)glutaranilic acid [8; R is CH ,CON(CH;,), R is HOCH CH R" is H, Y is CH CH CH- EXAMPLE 26 18 methylglutaramic acid) (B; R is HOOCCH CH CH- ,CON(CH;,). R' is CH;,, R is H, Y is CH CH CH disodium salt form. colorless prisms, m.p. 241245C by methylation of N,N-( 2,4,6-triiodo-m-phenylene )diglutaramic acid (Example l4b).

Example 28: 2,4,6-Triiodo-3-( N-methylacetamido N-methylsuccinanilic Acid [B; R is CH CON(CH R is CH R" is H, Y is CH CH m.p. l99-200C. from aqueous acetic acid; sodium salt form, m.p. l-190C. from methanol-ether, by

methylation of 2,4,6 -triiodo- 3 N- methylacetamido)succinanilic acid (Example 1 lb).

Example 29: 2,4,6'-Triiodo-3 N-methylacetamido 3,N-dimethylglutaranilic Acid B; R is CH CON(CH R is CH R" is H. Y is 2 3) 2lv colorless powder, mp. l0ll07.5C., by methylation of 2,4,6'-triiodo-3-(N-methylacetamido)-3-methylglutaranilic acid (Example 13b).

Example 30: {N Methyl-N-[ 2,4,6-triiodo-3-( N- methylacetamido )-phenyl ]carbamoylmethylthio} acetic Acid [8; R is CH;,CON(CH R is CH;,, R is H, Y is CH SCH tan solid, mp. l24l29C., prepared by hydrolysis of 4-[2,4,6-triiodo-3-(N-methylacetamido)phenyl]-3,5-

thiamorpholinedione and methylation of the resulting iN[ 2.4,6-triiodo-3-( N-methylacetamido )phenyl ]carbamoylmethylthiolacetic acid.

Example 31: 2,4',6-Triiodo-3 N-methylacetamido N-methyldiglycolanilic Acid [8; R is CH CON(CH R is CH;,, R is H, Y is CH OCH I,

colorless solid, mp. l4l-l 43C.. prepared by hydroly sis of N-[2,4,6-triiodo-3-( N-methylacetamido )phenyl diglycolimide, and methylation of the resulting 2,4,6-

triiodo-3-( N-methylacetamido)diglycolanilic acid.

EXAM PLE 32 a. N,N'-(2,4.6-Triiodo-a,m-toluylene)bis[acetamide1 [K; R is CH CONHCH Q is COCH was prepared by decarboxylation of 3-acetamido-5- acetamidomethyl-2,4,6-triiodobenzoic acid according to the method of Example 1(b), and was obtained in the form of a colorless solid. mp. 287288C. when recrystallized from acetic acid.

b. N-[ 2,4,6-Triiodo-3-( acetylaminomethyl )phenyl]- glutarimide [A; R is CH CONHCH Y is CH CH CH was prepared by interacting a-acetamido-2,4',6-triiodo-m-acetotoluidide with glutaric anhydride according to the method of Example 2(a), and was obtained in the form of a colorless solid, mp. l'28l34C. when recrystallized from isopropyl alcohol.

EXAMPLE 33 a. N-[2,4,6-Triiodo-3-(acetylaminomethyl)-5-carboxyphenyllglutarimide [C; R is CHgCONHCHg, Y is CH CH CH was prepared by interacting 3-acetamido-5- acetamidomethyl-2,4,6-triiodobenzoic acid with glutaric anhydride according to the method of Example 2(a), and was obtained in the form of a colorless solid,

mp. 256258C. when recrystallized from acetic acid.

b. N-[2,4,6-Triiodo-3-( acetylaminomethyl)-5-carboxyphenyl]glutaramic Acid [D; R is CH CONHCH R and R are H, Y is CH CH CH was prepared by hydrolysis of N-[2,4,6-triiodo-3- (acetylaminomethyl )5 -carboxyphenyl glutarimide with dilute sodium hydroxide, and was obtained in the form of a colorless solid, mp. 23-'1"239"Cv when recrystallized from acetic acid.

c. N-[ 2,4,6-Triiodo-3-( acetylaminomethyl )phenyl glutaramic Acid [8; R is CH CONHCH R and R" are H, Y is CH CH CH was prepared by decarboxylation of N-[2,4,6-triiodo-3 (acetylaminomethyl )-5-carboxyphenyllglutaramic acid according to the method of Example l(b and was obtained in the form of a colorless solid, mp. 254-259C. when recrystallized from aqueous dimethylformamide. The same substance can be prepared by hydrolysis of N-[2,4,6-triiodo-3-(acetylaminomethyl)- phenyllglutarimide (Example 32b) with warm dilute sodium hydroxide.

EXAMPLE 34 N-[2,4.6-Triiodo-3-( acetylaminomethyl )phenyl I-N methylglutaramic Acid [8; R is CH CONHCH R is CH R" is H, Y is CH CH CH l was prepared by interacting N-[2,4,6-triiodo-3- (acetylaminomethyl )phenyllglutaramic acid (Example 33c) with dimethyl sulfate according to the procedure of Example 23, and was obtained in the form ofa colorless solid, mp. l67l75C. when recrystallized from ethyl acetate.

EXAMPLE 35 a. Methyl 3 -carboxy-2 ,4,6'-triiodo-5 N- methylacetamido )azelanilate [D; R is CH,,CON(CH- l. R is H. R" is CH Y is (CH l:l A mixture of l()() g. of azelaic acid monomethyl ester and 500 ml. of thionyl chloride was refluxed for one hour. The excess thionyl chloride was removed by distillation and the last traces removed by adding benzene and evaporating the solvent. A solution of 260 g. of 3-amino-5-acetamido-2,4,6-triiodobenzoic acid in 3500 ml. of dioxane was then added to the resulting acid chloride of azelaic acid monomethyl ester, and the mixture was refluxed for six hours. The dioxane was then removed by distillation and the residual product recrystallized from acetic acid to give methyl 3-carboxy-2 ,4 ',6'-triiodo-5-( N-methylacetarnido )azelanilate, as colorless needles, mp. l98-203C.

By replacing the azelaic acid monomethyl ester by a molar equivalent amount of oxalic acid monomethyl ester or malonic acid monomethyl ester. there can be obtained, respectively, methyl 3-carboxy-2,4,6-triiod-5-(N-methylacetamido)oxalanilate [D; R is CH CON(CH R is H, R is CH Y is single bond], or methyl 3 '-carboxy-2,4,6'-triiodo-5 N- methylacetamido )malonan ilate [D; R is CH CON(CH R is H. R" is CH Y is -CH l. b. 3 -Carb0xy-2 ,4,6-triiodo- N- methylacetamido)azelanilic Acid [D; R is A mixture of 136.5 g. of methyl 3-carboxy-2,4,6- triiodo-5 Nmethylacetamido)azelanilate and 180 ml. of water was treated with l07r aqueous sodium hydroxide (about [40 ml), added dropwise until solution was complete. The mixture was heated on a steam bath for 10 minutes, 18 ml. more of l()% sodium hy droxide was added, and the mixture heated one hour longer. The reaction mixture was cooled. acidified with 3% hydrochloric acid, and the solid product collected, washed with water. dried and recrystallized from acetic acid to give 3-carboxy-2,4,6-triiodo-5'-(N methylacetamido)azelanilic acid as a colorless solid, mp. BOT-208C.

By replacing the methyl 3-carboxy-2,4,6-triiodo 5-(N-methylacetamido)azelanilate by a molar equivalent amount of methyl 3-carboxy-2,4',6-triiodo-5- (N-methylacetamido )oxalanilate or methyl 3-carboxy- 2,4,6 triiodo-5 N-methylacetamido)malonanilatc there can be obtained, respectively, 3-carboxy-2,4,- 6-triiodo-5 N-methylacetamido )oxalanilic acid D; R is CH -,CON(CH.-;). R and R are H, Y is single bond] or 3 -carboxy-2 ,4',6'-triiodo-5 N- methylacetamido)malonanilic acid [D; R is CH CON(CH R and R are H, Y is CH.,].

c. 2',4,6-Triiodo-3'-(N-methylacetamido)azelanilic Acid [8-, R is CH CON(CH R and R" are H, Y is 2)7l was prepared by decarboxylation of 3-carboxy-2',4',-

6-triiodo5 N-methylacetamido )azelanilic acid according to the method of Example l(b), and was obtained in the form of a colorless solid, mp. l53-l60C.

By replacing the 3-carboxy-2,4,6-triiodo-5-(N- methylacetamido)azelanilic acid by a molar equivalent amount of 3 -carboxy-2 ,4,6-triiodo-5 N- methylacetamido)oxalanilic acid and 3-carboxy-2,- 4,6-triiodo-5 N-methylacetamido )malonanilic acid there can be obtained, respectively, 2,4',6-triiodo-3- (I -methylacetamido)oxalanilic acid [8; R is CH CONH(CH R and R are H, Y is single bond] or 2,4,6-triiodo-3 N-methylacetamido)malonanilic acid [8; R is CH CONH(CH3l, R and R are H, Y is CH l.

Alternatively, 2',4,6'-triiodo-3"(N- methylacetamido)azelanilic acid can be prepared by interacting 3-amino-2.4,6-triiodo-N-methylacetanilide [K; R is CH CON(CH3). Q is H} with the acid chloride or azelaic acid monomcthyl ester, and subjecting to mild alkaline hydrolysis the resulting methyl 2,4,6- triiodo-5-(N-methylacetamido)azelanilate [B; R is CH CON(CH R is H, R" is CH Y is (CH d. 2 ,4 ,6-Triiodo-N-methyl-3 N- methylacetamido)azelanilic Acid {8; R is was prepared by methylation of 2',4,6-triiodo-3 (N-methylacetamido)azelanilic acid with dimethyl sulfate according to the procedure of Example 23,

and was obtained in the form of its sodium salt, colorless solid, mp. above C.

EXAMPLE 36 a. N-Methyl-N,N 2,4,o-triiodo-m-phenylene)bis- [acetamide] [K; R is CH;,CON(CH Q is COCH was prepared by decarboxylation of 3-acetamido-5-( N- methylacetamido)-2,4,6-triiodobenzoic acid according to the procedure of Example l(b), and was obtained in the form ofa colorless solid, mp. C.

b. 3-Maleimido2,4,6-triiodo-N-methylacetanilide [A;

R is CH CON(CH Y is CH=CH] can be prepared by interacting 2,4,6-triiodo-N-methylmbenzenediacetamide with maleic anhydride according to the procedure of Example 2(a), or by decarboxylation of 2,4,6-triiodo-3-maleimido 5-( N methylacetamido)benzoic acid, mp. 312C. (dec.).

c. 5-(N-Mcthylacetamido)-2',4,6'-triiodomaleanilic Acid [3; R is CH,-,CON(CH R and R are H, Y is CH=CH] can be prepared by hydrolysis of 3maleimido'2,4,6-

triiodo-N-methylacetanilide with dilute sodium hydroxide.

EXAMPLE 37 N,N-( 2,4,fi-Triiodo-m-phenylene)bis-diglycolimide (A; R is Y is CH OCH can be prepared by heating together at l-l50C. 3-amino-2,4,6-triiodoaniline and diglycolic anhydride.

EXAMPLE 38 NN 2.4,-Triiodo-m-phenylene )bis( 3 .S-dioxothiomorpholine) [A; R is Y is CH SCH can be prepared by heating together at l20-150C. 3-amino-2,4,6-triiodoaniline and thiodiacetic anhydride. The latter can be oxidized with m-chloroperbenzoic acid in dimethylformamide solution to afford N,N-( 2,4,6-triiodo-m-phenylene )bis( 3 ,5 ,S-trioxothiomorpholine) [A; R is cH co Y is CH SOCH and N,N'-(2,4,6-triiodo-mphenyle ne )bis( 3,5,S,S-tetraoxothiomorpholine) (A; Ris

cn co Y is CH SO CH-z].

EXAMPLE 39 N,N'-(2,4,6-Triiodo-m-phenylene)dimaleimide [A; R

Y is -CH=CH-] can be prepared by interacting 3-amino-2,4,6-triiodoaniline and maleic anhydride according to the procedure of Example 2(a).

I claim:

I. A compound of the formula 3,5-thiamorpholinedione, according to claim 2.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 1 3,926,975

DATED 1 December 16, 1975 INVENTORUS) James H. Ackerman it rs certrfred that error appears rn the above dentrfied patent and that sard Letters Patent are hereby corrected as shown beiow Column 6, line 26, "period" should read --peracid-.

Signed and fizzled this twenty-third Of March 1976 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner of Parents and Trademarks 

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 wherein R is (lower-alkanoyl)N(lower-alkyl).
 3. N-(2,4,6-Triiodo-3-(N-methylacetamido)phenyl)diglycolimide, according to claim
 2. 4. 4-(2,4,6-Triiodo-3-(N-methylacetamido)phenyl)-3,5-thiamorpholinedione, according to claim
 2. 